This proposal includes the development of a novel integrated sensor for simultaneous, long-term recording of activity from multiple neurons at multiple locations within a tissue explant. There are three specific aims: 1) to use, for the first time, complimentary metal-oxide semiconductor (CMOS) processing to integrate into a microchip a dense array of microelectrodes and amplification circuitry; 2) to develop signal processing techniques to identify and track cells in both space and time; and 3) to apply the array to the study of a neuronal oscillator. Specifically, 400 thin-film microelectrodes will be micromachined to record extracellular action potentials. To sample activity in three-dimensions of the cultured explant, the electrodes will terminate in a 20 by 20 array of tips spaced 40 microns apart with 25 of the central electrodes protruding 20 microns above the others. Neural signals will pass to embedded operational amplifiers within 500 microns of each electrode. The electrode array will be packaged inside a cell-culture chamber and plugged into a printed circuit board. The data acquisition system, employing template-matching software, will automatically locate, discriminate, and track neural activity even from intermittently active cells on the microchip. The innovative application of CMOS fabrication technology will produce an array of electrodes that samples neural activities at the highest possible spatial resolution over an area large enough to compare activities inside and outside a tissue of interest. The method will yield increased ease of use, increased number of recordings per preparation, and decreased space requirements for a laboratory setup. Importantly, the method uses materials that are biocompatible and standard in cell culture, and facilitates mass production at low cost. The integrated circuitry will drastically enhance the signal-to-noise ratio and reduce the cost of multi-site extracellular recording. The application of micromachining technologies to neural recording should produce new scalable electrode arrays that will be useful in addressing a wide variety of neurobiological questions that are currently intractable.